The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a xe2x80x9cCAAXxe2x80x9d or xe2x80x9cCys-Aaa1-Aaa2-Xaaxe2x80x9d box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen, et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively. (S. Clarke, Ann. Rev. Biochem. 61:355-386 (1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). The term prenyl-protein transferase may be used to generally refer to farnesyl-protein transferase and geranylgeranyl-protein transferase. The Ras protein is one of several proteins that are known to undergo post-translational farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of farnesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly (N. E. Kohl et al., Science, 260:1934-1937 (1993) and G. L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of ras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck and Co., Rahway, N.J.) and compactin (Hancock, et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of farnesyl-protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of farnesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates (e.g., Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). In general, deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound. However, the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of farnesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 A1).
It is, therefore, an object of this invention to develop peptidomimetic compounds that do not have a thiol moiety, and that will inhibit prenyl-protein transferase and thus, the post-translational prenylation of proteins. It is a further object of this invention to develop chemotherapeutic compositions containing the compounds of this invention and methods for producing the compounds of this invention.
The present invention is directed to peptidomimetic compounds that comprise bicyclic imidazolyl moieties and that inhibit the prenyl-protein transferase. Further contained in this invention are chemotherapeutic compositions containing these prenyl-protein transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the formula A: 
The compounds of this invention are useful in the inhibition of prenyl-protein transferase and the prenylation of the oncogene protein Ras. In a first embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula A: 
wherein:
R1 and R2a are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94,
c) unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl or unsubstituted or substituted C2-C6 alkynyl, wherein the substituent on the substituted C1-C6 alkyl, substituted C2-C6 alkenyl or substituted C2-C6 alkynyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, and R11OC(O)xe2x80x94NR10xe2x80x94, or
two R1s or two R2as, on the same carbon atom may be combined to form xe2x80x94(CH2)txe2x80x94;
R2 is independently selected from H; unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, 
xe2x80x83wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
e) CN,
2) C3-6 cycloalkyl,
3) OR6,
4) SR4, S(O)R4, SO2R4, 
two R2s attached to the same carbon atom are combined to form xe2x80x94(CH2)uxe2x80x94 wherein one of the carbon atoms is optionally replaced by a moiety selected from O, S(O)m, xe2x80x94NC(O)xe2x80x94, and xe2x80x94N(COR10)xe2x80x94;
R3 is selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, (R10)2Nxe2x80x94C(O)xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94 or R10OC(O)xe2x80x94, and
c) unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl or unsubstituted or substituted C2-C6 alkynyl, wherein the substituent on the substituted C1-C6 alkyl, substituted C2-C6 alkenyl or substituted C2-C6 alkynyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, one or more fluorines, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(O)xe2x80x94, CN, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, and R11OC(O)xe2x80x94NR10xe2x80x94;
R4 is selected from C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11 
g) N(R10)2, or
h) one or more fluorines;
R5, R6 and R7 are independently selected from:
1) hydrogen,
2) R10C(O)xe2x80x94, or R10OC(O)xe2x80x94, and
3) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more substituents selected from:
a) R10Oxe2x80x94,
b) aryl or heterocycle,
c) halogen,
d) R10C(O)NR10xe2x80x94, 
f) xe2x80x94SO2R11,
g) N(R10)2,
h) C3-6 cycloalkyl,
i) C1-C6 perfluoroalkyl,
j) (R10)2Nxe2x80x94C(NR10)xe2x80x94,
k) R10OC(O)xe2x80x94,
l) R11OC(O)NR10xe2x80x94,
m) CN, and
n) NO2; or
R6 and R7 may be joined in a ring; and independently,
R5 and R7 may be joined in a ring;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R12Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NHxe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R10OC(O)NHxe2x80x94;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, NO2, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, Br, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2NC(O)xe2x80x94, R102Nxe2x80x94C(NR10)xe2x80x94, CN, R10C(O)xe2x80x94, R10OC(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, benzyl, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R11 is independently selected from C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, unsubstituted or substituted aryl and unsubstituted or substituted heterocycle;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
V is selected from:
a) heterocycle, and
b) aryl;
W is S(O)m, O or CH2;
X is selected from: a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94S(O)2N(R10)xe2x80x94, xe2x80x94(R10)S(O)2Nxe2x80x94, O and S(O)2;
Y is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94 and xe2x80x94S(O)m;
Z is selected from unsubstituted or substituted aryl and unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7, or
h) one or more fluorines;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3;
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is independently 0, 1 or 2;
n is 1, 2 or 3;
p is independently 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3;
t is 2, 3, 4, 5 or 6; and
u is 2, 3, 4 or 5;
or a pharmaceutically acceptable salt or stereoisomer thereof.
Another embodiment of the compounds of this invention is illustrated by the formula B: 
wherein:
R1 and R2a are independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94, R11OC(O)Oxe2x80x94 or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl, unsubstituted or substituted by R10Oxe2x80x94, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94, R11OC(O)Oxe2x80x94, R11OC(O)NR10xe2x80x94 or R11S(O)mxe2x80x94;
R2 is selected from H; 
xe2x80x83and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR4, SO2R4, or 
R3 is selected from:
a) hydrogen, and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from one or more fluorines, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, R10OC(O)Oxe2x80x94 and R11OC(O)xe2x80x94NR10xe2x80x94;
R4 is selected from:
C1-4 alkyl and C3-6 cycloalkyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) one or more fluorines, or
c) aryl or heterocycle;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2, or
h) C3-6 cycloalkyl;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by: unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, and unsubstituted or substituted aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with one or more fluorines, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
V is selected from:
a) heterocycle selected from pyridinyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl, and
b) aryl;
W is S or CH2;
X is selected from a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94 or xe2x80x94S(xe2x95x90O)m;
Y is selected from a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10C(O)xe2x80x94C(O)Oxe2x80x94 and xe2x80x94S(xe2x95x90O)m;
Z is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is independently substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7, or
h) one or more fluorines;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 2, 3, 4, 5 or 6;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In another embodiment of this invention, the inhibitors of prenyl-protein transferase are illustrated by the formula C: 
wherein:
R1 and R2a are independently selected from:
a) hydrogen,
b) R10Oxe2x80x94, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94, R11OC(O)Oxe2x80x94 or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl, unsubstituted or substituted by R10Oxe2x80x94, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94, R11OC(O)Oxe2x80x94, R11OC(O)NR10xe2x80x94 or R11S(O)mxe2x80x94;
R2 is selected from H; 
xe2x80x83and C1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR4, SO2R4, or 
R3 is selected from:
a) hydrogen, and
b) unsubstituted or substituted C1-C6 alkyl, wherein the substituent on the substituted C1-C6 alkyl is selected from one or more fluorines, R10Oxe2x80x94, R11S(O)mxe2x80x94, R10C(O)NR10xe2x80x94, R10OC(O)Oxe2x80x94 and R11OC(O)xe2x80x94NR10xe2x80x94;
R6 and R7 are independently selected from H; C1-6 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or two:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO, 
f) xe2x80x94SO2R11,
g) N(R10)2, or
h) C3-6 cycloalkyl;
R8 is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R12Oxe2x80x94, R10C(O)NR10xe2x80x94, CN, NO2, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94, and
c) C1-C6 alkyl substituted by: unsubstituted or substituted aryl, C1-C6 perfluoroalkyl, R10Oxe2x80x94, R10C(O)NR10xe2x80x94, (R10)2Nxe2x80x94C(NR10)xe2x80x94, R10C(O)xe2x80x94, xe2x80x94N(R10)2, or R11OC(O)NR10xe2x80x94;
R10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines, benzyl and unsubstituted or substituted aryl;
R11 is independently selected from C1-C6 alkyl, C1-C6 alkyl substituted with one or more fluorines and unsubstituted or substituted aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, and C1-C6 alkyl substituted with one or more fluorines, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle;
W is S or CH2;
X is selected from a bond, xe2x80x94NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 and xe2x80x94NR10C(O)xe2x80x94;
Y is selected from a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(O)NR10xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94C(O)Oxe2x80x94 and xe2x80x94S(xe2x95x90O)m;
Z is selected from unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted aryl or substituted heterocycle is independently substituted with one or two of:
1) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
f) xe2x80x94S(O)mR4,
g) xe2x80x94C(O)NR6R7, or
h) one or more fluorines;
2) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
3) halogen,
4) OR6,
5) NR6R7,
6) CN,
7) NO2,
8) CF3,
9) xe2x80x94S(O)mR4,
10) xe2x80x94OS(O)2R4,
11) xe2x80x94C(O)NR6R7,
12) xe2x80x94C(O)OR6, or
13) C3-C6 cycloalkyl;
m is 0, 1 or 2;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5;
s is independently 0, 1, 2 or 3; and
t is 2, 3 or 4;
or a pharmaceutically acceptable salt or stereoisomer thereof.
Examples of the compounds of the invention are:
N-(2-Phenylsulfonyl-1-ethyl) 3-(4-Cyanophenyl)-2,3-dihydro-imidazo[2,1-b]thiazole-5-carboxamide
N-(2-Phenylthio-1-ethyl) 3-(4-Cyanophenyl)-2,3-dihydro-imidazo[2,1-b]thiazole-5-carboxamide
N-(2-Phenyloxy-1-ethyl) 3-(4-Cyanophenyl)-2,3-dihydro-imidazo[2,1-b]thiazole-5-carboxamide
N-(3-Phenylpropyl) 3-(4-Cyanophenyl)-2,3-dihydro-imidazo[2,1-b]thiazole-5-carboxamide
N-(3-(3-Hydroxyphenylsulfonyl-1-propyl)) 3-(4-cyanophenyl)-2,3-dihydro-imidazo[2,1-b]thiazole-5-carboxamide
Methyl N-{2-[(3-chlorophenyl)amino]ethyl}-N-{[3-(4-cyanophenyl)-2,3-dihydroimidazo[2,1-b][1,3]thiazol-5-yl]carbonyl}glycinate
or the pharmaceutically acceptable salts or stereoisomers thereof.
The compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention. (See E. L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190) When any variable (e.g. aryl, heterocycle, R1a, R6 etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein means fluoro, chloro, bromo and iodo.
Preferably, alkenyl is C2-C6 alkenyl.
Preferably, alkynyl is C2-C6 alkynyl.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is intended to include cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Preferably, cycloalkyl is C3-C10 cycloalkyl. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, xe2x80x9carylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocycle or heterocyclic, as used herein, includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, 2-pyridinonyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl and triazolyl.
As used herein, xe2x80x9cheteroarylxe2x80x9d is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl and triazolyl.
As used herein, unless otherwise specifically defined, substituted alkyl, substituted cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted heteroaryl, substituted arylsulfonyl, substituted heteroaryl-sulfonyl and substituted heterocycle include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, such substituents are selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C1-C6 alkyl)2, NO2, CN, (C1-C6 alkyl)Oxe2x80x94, (aryl)Oxe2x80x94, xe2x80x94OH, (C1-C6 alkyl)S(O)mxe2x80x94, (C1-C6 alkyl)C(O)NHxe2x80x94, H2Nxe2x80x94C(NH)xe2x80x94, (C1-C6 alkyl)C(O)xe2x80x94, (C1-C6 alkyl)OC(O)xe2x80x94, (C1-C6 alkyl)OC(O)NHxe2x80x94, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.
As used herein, the term xe2x80x9cone or more fluorinesxe2x80x9d describes substitution on one or more carbon atoms of a substituted group with one or more fluroine atoms. Preferably the substituted group which is substituted with one or more fluorines is substituted with one to five fluorines. Preferably a C1-6 alkyl substituted with one or more fluorines is a C1-6 alkyl substituted with one to five fluorines.
Preferably, as used herein in the definition of R6 and R7, the substituted C1-6 alkyl, substituted C2-6 alkenyl, substituted C2-6 alkynyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle, include moieties containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
The moiety formed when, in the definition of R1, R2 and R2a, two R1s, two R2s or two R2as, on the same carbon atom are combined to form xe2x80x94(CH2)uxe2x80x94 is illustrated by the following: 
In addition, such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to: 
The moiety formed when, in the definition of R6, R7 and R7a, R6 and R7 or R7 and R7a are joined to form a ring, is illustrated by, but not limited to, the following: 
Lines drawn into the ring systems from substituents (such as from R8, R9 etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon and nitrogen atoms.
Preferably, R1 and R2a are independently selected from: hydrogen, xe2x80x94N(R10)2, R10C(O)NR10xe2x80x94 or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, xe2x80x94N(R10)2, R10Oxe2x80x94 and R10C(O)NR10xe2x80x94. More preferably, R1 and R2a are hydrogen.
Preferably, R2 is selected from H, 
and an unsubstituted or substituted C1-8 alkyl,
wherein the substituted C1-8 alkyl is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) OR6,
4) SR4, S(O)R4, SO2R4, 
15) N3, or
16) F.
Preferably, R3 is selected from: hydrogen, or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted phenyl, xe2x80x94N(R10)2, R10Oxe2x80x94 and R10C(O)NR10xe2x80x94.
Preferably, R4 is C1-C6 alkyl.
Preferably, R6 and R7 is selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
Preferably, R9 is hydrogen or methyl.
Preferably, R10 is selected from H, C1-C6 alkyl and benzyl.
Preferably, V is selected from heteroaryl and aryl. More preferably, V is phenyl or pyridyl.
Preferably, X is selected from xe2x80x94NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 and xe2x80x94NR10C(O)xe2x80x94 and xe2x80x94N(R10)S(O)2xe2x80x94.
Preferably, Y is selected from xe2x80x94NR10xe2x80x94, xe2x80x94C(O)NR10xe2x80x94 and xe2x80x94NR10C(O)xe2x80x94 and xe2x80x94S(O)2N(R10)xe2x80x94.
Preferably, Z is selected from unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl. More preferably, Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted pyridyl, unsubstituted or substituted furanyl and unsubstituted or substituted thienyl. Still more preferably, Z is selected from unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl.
Preferably, W is selected from S and CH2.
Preferably, n is 1 or 2.
Preferably, r is 1 or 2.
Preferably p is 0, 1 or 2.
Preferably s is 0 or 1.
Preferably, the moiety 
is selected from: 
It is intended that the definition of any substituent or variable (e.g., R1, R9, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, xe2x80x94N(R10)2 represents xe2x80x94NHH, xe2x80x94NHCH3, xe2x80x94NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-14, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R, Ra, Rb, R9xe2x80x2, R9xe2x80x3, Z and Rsub, as shown in the Schemes, represent the substituents R2, R3, R9 and Z, and substituents on Z, or their synthetic precursors; however their point of attachment to the ring is illustrative only and is not meant to be limiting. It is understood that one of ordinary skill in the art would be readily able to substitute commercially available or readily prepared suitably substituted aromatic moieties for those unsubstituted moieties illustrated in the schemes.